Inosine derivatives and production methods therefor

ABSTRACT

The present invention provides a method for producing an inosine derivative represented by the following general formula (1) including the steps of subjecting an inosine derivative of general formula (3) to dithiocarbonylation and carrying out radical reduction of the obtained compound. According to the present invention there can be produced compounds useful as anti-AIDS drugs on industrial scale. 
                         
wherein R1 may be the same or different and are each benzyl group, benzhydryl group or trityl group, each of which may have a substituent in general formulas (1) and (3).

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of International applicationPCT/JP2004/008783, filed on Jun. 16, 2004, which claims priority to JP2003-170361, filed on Jun. 16, 2003.

BACKGROUND OF THE INVENTION

The present invention relates to methods for producing2′,3′-dideoxyinosine useful as an antiviral agent, represented by thefollowing formula (7), (which is called didanosine (DDI) and hereinafterreferred to as “DDI”), intermediate compounds that are essential inproducing the DDI, and methods for producing the intermediate compounds.

DDI is useful as an antiviral agent and has already been approved as ananti-AIDS drug in many countries including the U.S.A., Japan andEuropean countries.

To obtain a dideoxy (DD) derivative from nucleoside, there isconventionally known, for example, a method where hydroxyl groups at the2′- and 3′-positions of nucleoside are subjected to thiocarbonylation,followed by radical reduction to form a didehydrodideoxy (D4)derivative, and the D4 derivative is subjected to hydrogenation or thelike, thereby obtaining a dideoxy (DD) derivative. Some synthesismethods for various antiviral agents based on the above-mentionedtechnique are reported, which include a method described in: Chu, C. K.et, al. J. Org. Chem. 1989, 54, 2217-2225. However, the method describedin the aforementioned literature needs a step of protecting a hydroxylgroup at the 5′-position of nucleoside in advance. For example, whenadenosine is used as a raw material for the production of the DDderivative, tert-butyldimethylsilyl group (e.g., refer to Chu, C. K. et,al. J. Org. Chem. 1989, 54, 2217-2225) and trityl group (e.g., refer toYurkevich, A. M. et al. Tetrahedron, 1969, 25, 477-484) are adopted asthe protective groups. However, when the DDI is produced using inosineas a raw material, the aforementioned protective groups cause theproblems shown below. Namely, as for the tert-butyldimethylsilyl group,it is expensive and a fluorine-based reagent becomes necessary in theprocess of deprotection. The use of trityl group prevents the progressof the reaction with satisfactory yields (e.g., refer to Japanese PatentUnexamined Publication (JP Kokai) Hei 07-109290). In light of the above,there is an increasing demand for development of methods for producingDDI (7) and 2′,3′-didehydro-2′,3′-dideoxyinosine (4) (which is called D4inosine and hereinafter referred to as “D4I”) inexpensively so as toobtain satisfactory yields.

There is known a compound where amino group and hydroxyl grouprespectively at the 1-position and the 5′-position of inosine areprotected by benzyl (e.g., Luzzio, F. A. et al. J. Org. Chem., 1994, 59,7267-7272). However, nothing has been known about a production methodfor the DDI from the above-mentioned compound as a raw material bysubjecting two hydroxyl groups at the 2′- and 3′-positions todeoxylation.

DISCLOSURE OF INVENTION

Objects of the present invention are to provide methods for producingDDI (7), D4I (4) and derivatives thereof in good yields.

After intensive researches and studies, the inventors of the presentinvention newly found that an inosine derivative represented by thefollowing general formula (1) can be derived from5′-O-benzyl-N¹-benzylinosine derivative that has been synthesized inaccordance with a method, for example, as described in Luzzio, F. A. etal. J. Org. Chem., 1994, 59, 7267-7272, by subjecting the raw materialto thiocarbonylation of hydroxyl groups at the 2′- and 3′-positions andsubsequently carrying out radical reduction. The present invention hasbeen accomplished based on the above-mentioned finding. Namely, thepresent invention provides a method for producing an inosine derivativerepresented by the following general formula (1),

comprising the steps of subjecting an inosine derivative of thefollowing general formula (3) to dithiocarbonylation to obtain acompound, and subjecting the obtained compound to radical reduction:

wherein R1 may be the same or different and are each benzyl group,benzhydryl group or trityl group, each of which may have a substituentin general formula (1) and (3).

Also, the present invention provides a method for producing an inosinederivative represented by the following general formula (2), comprisingthe step of hydrogenating the inosine derivative represented by theabove-mentioned general formula (1):

wherein R1 may be the same or different and are each benzyl group,benzhydryl group or trityl group, each of which may have a substituent.

The present invention also provides a method for producing2′,3′-dideoxyinosine (DDI), characterized by hydrogenating the inosinederivative represented by the above-mentioned general formula (1) or theinosine derivative represented by the above-mentioned general formula(2).

In addition, the present invention provides a method for producing2′,3′-didehydro-2′,3′-dideoxyinosine (D4I) represented by theabove-mentioned general formula (4), comprising the step of eliminatingsubstituents R1 from the inosine derivative represented by theabove-mentioned general formula (1).

Further, the present invention provides a method for producing2′,3′-dideoxyinosine (DDI), comprising the steps of:

subjecting the inosine derivative represented by the above-mentionedgeneral formula (3) to dithiocarbonylation to obtain a compound of thefollowing general formula (5):

wherein R1 may be the same or different and are each benzyl group,benzhydryl group or trityl group, each of which may have a substituent;and R2 are each an alkylthio group having 1 to 12 carbon atoms, analkoxyl group having 1 to 12 carbon atoms or an alkylamino group having1 to 12 carbon atoms;

subjecting the compound of the general formula (5) to radical reductionto obtain the inosine derivative represented by the above-mentionedgeneral formula (1);

hydrogenating the inosine derivative represented by the general formula(1) to obtain the compound represented by the above-mentioned generalformula (2); and

eliminating the substituents R1 from the compound represented by thegeneral formula (2).

Also, the present invention provides a method for producing2′,3′-didehydro-2′,3′-dideoxyinosine (D4I) represented by theabove-mentioned general formula (4), comprising the steps of:

subjecting the inosine derivative represented by the above-mentionedgeneral formula (3) to dithiocarbonylation to obtain the compound of theabove-mentioned general formula (5);

eliminating the substituents R1 from the compound represented by thegeneral formula (5) to obtain a compound of the following generalformula (6):

wherein R2 are each an alkylthio group having 1 to 12 carbon atoms, analkoxyl group having 1 to 12 carbon atoms or an alkylamino group having1 to 12 carbon atoms; and

subjecting the compound of the general formula (6) to radical reduction.

Also, the present invention provides a method for producing2′,3′-didehydro-2′,3′-dideoxyinosine (D4I) represented by theabove-mentioned general formula (4), comprising the steps of subjectingthe inosine derivative represented by the above-mentioned generalformula (3) to dithiocarbonylation to obtain the compound of theabove-mentioned general formula (5), subjecting the compound of thegeneral formula (5) to radical reduction to obtain the inosinederivative represented by the above-mentioned general formula (1), andeliminating the substituents R1 from the inosine derivative representedby the general formula (1).

The present invention provides a method for producing DDI comprising thestep of hydrogenating 2′,3′-didehydro-2′,3′-dideoxyinosine (D4I)obtained by the above-mentioned methods, and 2′,3′-dideoxyinosine (DDI)obtainable by the above-mentioned production method.

Furthermore, the present invention provides inosine derivativesrepresented by the following general formula (1):

wherein R1 may be the same or different and are each benzyl group,benzhydryl group or trityl group, each of which may have a substituent.

The present invention also provides inosine derivatives represented bythe following general formula (2).

The present invention also provides inosine derivatives represented bythe following general formula (5).

The present invention also provides inosine derivatives represented bythe following general formula (6).

In general formulas (2), (5) and (6), R1 and R2 are the same as thosepreviously defined.

BEST MODE FOR CARRYING OUT THE INVENTION

In the aforementioned general formulas (1) through (3) and (5), R1 maybe the same or different and are each benzyl group, benzhydryl group ortrityl group, each of which may have a substituent. In particular,benzyl group which may have a substituent is preferable from theviewpoints of yield and economical efficiency. In the case where R1 hasa substituent, the position and the number of substituents are notparticularly limited. Examples of the substituents for R1 include analkyl group having 1 to 12 carbon atoms such as methyl group, ethylgroup, n-propyl group, i-propyl group, n-butyl group, i-butyl group,sec-butyl group, tert-butyl group or the like; a cycloalkyl groupshaving 3 to 12 carbon atoms such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group or the like; an alkoxyl group having1 to 12 carbon atoms such as methoxy group, ethoxy group, n-propoxygroup, i-propoxy group, n-butoxy group, tert-butoxy group or the like;an acyloxy group having 2 to 12 carbon atoms such as acetoxy group,benzoyloxy group or the like; hydroxyl group; a halogen atom such asfluorine, chlorine, bromine, iodine or the like; vinyl group; allylgroup; an aryl group such as phenyl group, naphthyl group, furyl group,indolyl group, pyridyl group or the like; a carbonyl group such asformyl group, acetyl group, trifluoroacetyl group, benzoyl group,methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group,vinyloxycarbonyl group, allyloxycarbonyl group, benzyloxycarbonyl group,methylaminocarbonyl group or the like; a sulfonyl group such asalkylsulfonyl group, arylsulfonyl group, sulfonamide or the like; aminogroup; a primary amino group such as N-methylamino group, N-ethylaminogroup, N-n-propylamino group, N-isopropylamino group, N-n-butylaminogroup, N-isobutylamino group, N-tert-butylamino group, N-benzylaminogroup, N-methoxycarbonylamino group, N-tert-butoxycarbonylamino group,N-phenylamino group, N-mesylamino group, N-tosylamino group,N-formylamino group or the like; a secondary amino group such asN,N-dimethylamino group, N,N-diethylamino group, N,N-dibenzylaminogroup, N-ethyl-N-methylamino group, N,N-di-n-propylamino group,N,N-diisopropylamino group, N,N-diphenylamino group,N-methyl-N-phenylamino group, N-methyl-N-benzylamino group,N-mesyl-N-methylamino group, piperidyl group, pyrrolidyl group or thelike; nitro group; nitroso group; cyano group; and a haloalkyl groupsuch as monofluoromethyl group, difluoromethyl group, trifluoromethylgroup, monochloromethyl group, dichloromethyl group, trichloromethylgroup, pentafluoroethyl group or the like. The alkoxyl group having 1 to12 carbon atoms is preferable as the substituent for R1. As the grouprepresented by R1, particularly preferable are unsubstituted benzylgroup and benzyl group having as a substituent an alkoxyl group with 1to 12 carbon atoms, preferably methoxy group, more preferably methoxygroup at the para-position.

The inosine derivative represented by the above-mentioned generalformula (1) can be produced, for example, by (i) subjecting the inosinederivative represented by the above-mentioned general formula (3) todithiocarbonylation to obtain the thiocarbonylated inosine derivative ofthe above-mentioned general formula (5), and (ii) carrying out theradical reduction of the obtained compound of general formula (5).

The inosine derivative represented by the above-mentioned generalformula (3) can be prepared, for example, by a conventional methoddescribed in the literature: Luzzio, F. A. et al. J. Org. Chem., 1994,59, 7267-7272. More specifically, hydroxyl groups at the 2′- and3′-positions of inosine are protected by ketal, and thereafter benzylgroup or the like is introduced into the obtained compound to achievedeprotection of the ketal, so that the inosine derivative of generalformula (3) can be produced. The amounts of raw materials, properreaction conditions, the kind and the amount of solvent, the catalystand the like are known to those skilled in the art.

In the above-mentioned formulas (5) and (6), R2 may be the same ordifferent, and are each an alkylthio group having 1 to 12 carbon atoms,an alkoxyl group having 1 to 12 carbon atoms, or an alkylamino grouphaving 1 to 12 carbon atoms. Each of those groups may have asubstituent. In consideration of the yield and economical efficiency, analkylthio group having 1 to 12 carbon atoms which may have a substituentis preferable. In the case where R2 has a substituent, the position andthe number of substituents are not particularly limited. Examples of thesubstituents for R2 include an alkoxyl group having 1 to 12 carbon atomssuch as methoxy group, ethoxy group, n-propoxy group, i-propoxy group,n-butoxy group, tert-butoxy group or the like; hydroxyl group; a halogenatom such as fluorine, chlorine, bromine, iodine or the like; aheteroaryl group such as furyl group, indolyl group, pyridyl group orthe like; a sulfonyl group such as alkylsulfonyl group, arylsulfonylgroup, sulfonamide or the like; amino group; a primary amino group suchas N-methylamino group, N-ethylamino group, N-n-propylamino group,N-isopropylamino group, N-n-butylamino group, N-isobutylamino group,N-tert-butylamino group, N-benzylamino group, N-phenylamino group,N-mesylamino group, N-tosylamino group or the like; a secondary aminogroup such as N,N-dimethylamino group, N,N-diethylamino group,N,N-dibenzylamino group, N-ethyl-N-methylamino group,N,N-di-n-propylamino group, N,N-diisopropylamino group,N,N-diphenylamino group, N-methyl-N-phenylamino group,N-methyl-N-benzylamino group, N-mesyl-N-methylamino group, piperidylgroup, pyrrolidyl group or the like; nitro group; nitroso group; cyanogroup, and so on. Particularly, cyano group is preferable as thesubstituent for R2. As the group represented by R2, methylthio group,and ethylthio group and 2-cyanoethylthio group are preferable, andmethylthio group is more preferable.

(i) In the present invention, the inosine derivative of general formula(3) is first subjected to dithiocarbonylation to obtain thethiocarbonylated inosine derivative represented by general formula (5).To achieve the step of dithiocarbonylation, the processes forthiocarbonylation, such as alkylthio-thiocarbonylation,alkoxy-thiocarbonylation, alkylamino-thiocarbonylation and the like canbe employed.

The process of alkylthio-thiocarbonylation can be carried out byallowing the inosine derivative of general formula (3) to react withcarbon disulfide and an alkyl halide in the presence of a base in anappropriate solvent. Examples of the solvent include dimethyl sulfoxide(DMSO), dimethylformamide (DMF), N-methylpyrrolidone, tetrahydrofuranand the like. In particular, DMSO is preferable. The amount of solventmay be preferably in the range of 0.5 to 5 L, more preferably 1 to 2 L,with respect to 1 mol of the inosine derivative of general formula (3).It is preferable that the amount of carbon disulfide be 2 to 4equivalent weights, more preferably 2 to 2.5 equivalent weights, withrespect to the inosine derivative of general formula (3). The baseincludes sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydride and the like, and sodium hydroxideand potassium hydroxide are preferably used. The amount of base may bepreferably 2 to 4 equivalent weights, more preferably 2 to 2.5equivalent weights, with respect to the inosine derivative of generalformula (3). Examples of the alkyl halide to be used include methyliodide, ethyl iodide, 2-cyanoethyl bromide and the like. In particular,methyl iodide and 2-cyanoethyl bromide are preferable. The amount ofalkyl halide is preferably 2 to 5 equivalent weights, more preferably 2to 3 equivalent weights, with respect to the inosine derivative ofgeneral formula (3). The reaction temperature, which varies dependingupon the kind of solvent, is generally in the range of −20 to 50° C.,preferably 0 to 30° C. It is preferable to carry out the reaction withinthe above-mentioned temperature range from the viewpoint of yield. Thereaction time is generally in the range of 0.1 to 10 hours, preferably 1to 3 hours. To cause the reaction within the above-mentioned time rangeproduces good results in terms of yield.

The process of alkoxy-thiocarbonylation can be carried out, for example,as described in WO173095, by allowing the inosine derivative of generalformula (3) to react with an alkoxy-thiocarbonyl halide in the presenceof a base in an appropriate solvent. Examples of the solvent includeorganic solvents such as acetonitrile, dimethylformamide (DMF),pyridine, ethyl acetate, toluene and the like. Acetonitrile ispreferable. The amount of solvent may be preferably in the range of 0.5to 5 L, more preferably 1 to 2 L, with respect to 1 mol of the inosinederivative of general formula (3). The base includes organic tertiaryamines such as pyridine, triethylamine, N-ethylpiperidine,N-ethylmorpholine and the like, and triethylamine and pyridine arepreferably used. The amount of base is preferably 2 to 4 equivalentweights, more preferably 2 to 2.5 equivalent weights, with respect tothe inosine derivative of general formula (3). The reaction temperature,which varies depending upon the kind of solvent, is generally in therange of −50 to 50° C., preferably −20 to 20° C. It is preferable tocarry out the reaction within the above-mentioned temperature range fromthe viewpoint of yield. The reaction time is generally in the range of0.1 to 5 hours, preferably 0.5 to 2 hours. To cause the reaction withinthe above-mentioned time range produces good results in terms of yield.

The process of alkylamino-thiocarbonylation can be carried out by amethod as described in, for example, Nishiyama, K. et al. TetrahedronLett., 2003, 44, 4027-4029, Izawa, K. et al. Tetrahedron Lett., 2001,42, 7605-7608, or the like. More specifically, the inosine derivative ofgeneral formula (3) may be allowed to react with phenyl isothiocyanateor 1,1′-thiocarbonyl diimidazole in an appropriate solvent, in thepresence of a base when necessary. Examples of the solvent includeorganic solvents such as dimethylformamide (DMF), tetrahydrofuran,acetonitrile and the like. In particular, dimethylformamide andtetrahydrofuran are preferable. The amount of solvent may be preferablyin the range of 0.5 to 5 L, more preferably 1 to 2 L, with respect to 1mol of the inosine derivative of general formula (3). The base includessodium hydride, sodium hydroxide, potassium hydroxide and the like, andsodium hydride is preferably used. The amount of base is preferably 2 to4 equivalent weights, more preferably 2 to 2.5 equivalent weights, withrespect to the inosine derivative of general formula (3). The reactionmay proceed in the absence of a base, and therefore the base is notalways necessary. The reaction temperature, which varies depending uponthe kind of solvent, is generally in the range of −20 to 100° C.,preferably 0 to 80° C. It is preferable to carry out the reaction withinthe above-mentioned temperature range from the viewpoint of yield. Thereaction time is generally in the range of 0.1 to 5 hours, preferably0.5 to 2 hours. To cause the reaction within the above-mentioned timerange produces good results in terms of yield.

(ii) According to the present invention, the compound of general formula(1) can be obtained by subjecting the compound represented by generalformula (5) to radical reduction.

Examples of the solvent that can be used in this step includedimethoxyethane (DME), acetonitrile, acetic ester, 1,4-dioxane,tetrahydrofuran (THF), and alcohols such as methanol, ethanol,2-propanol and the like. In particular, acetonitrile, 1,4-dioxane andtetrahydrofuran (THF) are preferable. The amount of solvent may bepreferably in the range of 0.5 to 5 L, more preferably 1 to 2 L, withrespect to 1 mol of the compound represented by general formula (5).

A radical reducing agent that can be used in this step includeshypophosphorous acid and salts thereof, for example, N-ethylpiperidinehypophosphite, tributyl tin hydride, silane compounds such as diphenylsilane, and the like. In particular, hypophosphorous acid and saltsthereof are preferable, and N-ethylpiperidine hypophosphite isparticularly preferable. The amount of radical reducing agent isgenerally 1 to 20 equivalent weights, preferably 1 to 5 equivalentweights, with respect to 1 mol of the compound obtained in the step (i).

A radical initiator that can be used in this step includesazobisisobutyronitrile (AIBN), triethylborane, and the like. Inparticular, AIBN is preferable. The amount of radical initiator isgenerally 0.01 to 2 equivalent weights, preferably 0.1 to one equivalentweight, with respect to 1 mol of the compound represented by generalformula (5).

The reaction temperature for this step, which varies depending upon thekind of solvent, is preferably in the range of 0 to 120° C., morepreferably 20 to 90° C. It is preferable to carry out the reactionwithin the above-mentioned temperature range from the viewpoint ofyield.

In this step, the reaction time is typically in the range of 0.1 to 10hours, preferably 1 to 5 hours. To cause the reaction within theabove-mentioned time range produces good results in terms of yield.

After the completion of the above-mentioned reaction in the presentinvention, the obtained product may be further purified bychromatography or the like.

(iii) According to the present invention, the compound represented bythe aforementioned general formula (2) can be produced by, for example,hydrogenating the compound represented by the aforementioned generalformula (1).

A catalyst that can be used in the present invention includespalladium-carbon, palladium hydroxide-carbon, platinum-carbon and thelike. In particular, palladium-carbon and palladium hydroxide-carbon arepreferable.

The atmospheric pressure of hydrogen is preferably in the range of 0.5to 10 atmospheres, more preferably 0.8 to 2 atmospheres.

Any organic solvents can freely be used for the solvent for use in thepresent invention. DMF, methanol, ethanol, acetonitrile andtetrahydrofuran are preferable, and methanol is particularly preferable.

The reaction temperature in the present invention, which variesdepending upon the kind of solvent, is preferably in the range of 10 to60° C., more preferably 20 to 50° C.

In this step, the reaction time is typically in the range of 0.1 to 10hours, preferably 1 to 5 hours.

After the completion of the above-mentioned reaction in the presentinvention, the obtained product may be further purified bychromatography or the like.

(iv) In the present invention, the intended DDI (7) can be derived fromthe inosine derivative represented by the above-mentioned generalformula (1) or (2) through hydrogenation. To be more specific, a doublebond in a sugar moiety of the inosine derivative represented by theabove-mentioned general formula (1) is subjected to hydrogenation, so asto derive the inosine derivative represented by the above-mentionedgeneral formula (2). Further, the protective groups R1 are eliminated byhydrogenolysis, thereby leading to the intended DDI. In this case,according to a preferred embodiment, a double bond in a sugar moiety ofthe inosine derivative represented by the above-mentioned generalformula (1) is subjected to hydrogenation in the presence of a metalcatalyst in an atmosphere of hydrogen so as to derive the inosinederivative represented by the above-mentioned general formula (2).Subsequently, a first benzyl group is eliminated in the presence of analkali at room temperature, and thereafter a second benzyl group iseliminated by the reaction where the pressure of hydrogen is increasedand/or the temperature is raised, thereby converting the inosinederivative of general formula (2) into the desired DDI. According to aparticularly preferable embodiment in this case, sodium hydroxide orpotassium hydroxide is used as an alkali, and the reaction time forelimination of the first benzyl group is in the range of 0.5 to 5 hours.The second benzyl group is eliminated under the conditions that thepressure of hydrogen is preferably set to 0.5 to 10 atmospheres, morepreferably 0.8 to 2 atmospheres, the temperature is set to 40 to 150°C., preferably 60 to 120° C., and the reaction time is set to 2 to 24hours.

(v) From the compound of aforementioned general formula (1), D4I (4) canalso be obtained by subsequent elimination of the substituentsrepresented by R1. This process is particularly useful in the case wherethe inosine derivative of general formula (3) is used as a startingmaterial where R1 is benzyl group having an alkoxyl group with 1 to 12carbon atoms, preferably methoxy group, more preferably methoxy group atthe para-position.

As an agent for eliminating the substituents R1 (i.e., deprotectingagent) that can be used in this step, diammonium cerium (IV) nitrate,2,3-dichloro-5,6-dicyano-1,4-benzoquinone and the like can be employed.In particular, diammonium cerium (IV) nitrate and2,3-dichloro-5,6-dicyano-1,4-benzoquinone are preferable. The amount ofthis agent is preferably in the range of 1 to 5 mol, more preferably 2to 3 mol, with respect to 1 mol of the compound of general formula (1).

Examples of the solvent that can be used in this step include a mixedsolvent of acetonitrile and water, a mixed solvent of dichloromethaneand water, tetrahydrofuran, and so on. In particular, a mixed solvent ofacetonitrile and water is preferable. The amount of solvent ispreferably in the range of 1 to 100 mL, more preferably 10 to 50 mL,with respect to 1 mol of the compound having general formula (1).

The reaction temperature for this step, which varies depending upon thekind of solvent, is preferably in the range of 0 to 100° C., morepreferably room temperature. It is preferable to carry out the reactionwithin the above-mentioned temperature range from the viewpoint ofyield. The reaction time for this step is typically in the range of 0.1to 10 hours, preferably 2 to 5 hours. To cause the reaction within theabove-mentioned time range produces good results in terms of yield. Thisstep can preferably give the D4I (4) in high yields.

After the completion of the reaction in this step, the obtained productmay be further purified by chromatography or the like.

(vi) In the present invention, a thiocarbonyl inosine represented bygeneral formula (6) is obtained by eliminating the substituents R1 fromthe compound of general formula (5). This process is particularly usefulin the case where the inosine derivative of general formula (3) is usedas a starting material where R1 is benzyl group having an alkoxyl groupwith 1 to 12 carbon atoms, preferably, methoxy group, more preferably,methoxy group at the para-position.

The same agent for eliminating the substituents R1 as used in the step(v) can be used in this step. In particular, diammonium cerium (IV)nitrate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are preferable.The amount of this agent is preferably in the range of 1 to 5 mol, morepreferably 2 to 3 mol, with respect to 1 mol of the compound havinggeneral formula (5).

The solvent that can be used in this step and the amount thereof, thereaction temperature, and the reaction time are the same as thosedescribed in the conditions of the step (iv), and the preferableconditions and the reasons therefor described in the step (iv) are alsoapplied to this case.

After the completion of the reaction in this step, the obtained productmay be further purified by chromatography or the like.

(vii) In the present invention, D4I (4) can be obtained by subjectingthe compound represented by general formula (6) to radical reduction.

The same radical reducing agents that can be used in the step (ii) areapplicable to this step. In particular, hypophosphorous acid and saltsthereof are preferable, and N-ethylpiperidine hypophosphite is morepreferable. The amount of radical reducing agent is preferably 1 to 20equivalent weights, more preferably 1 to 5 equivalent weights, withrespect to 1 mol of the compound of general formula (6).

Examples of the solvent that can be used in this step include a mixedsolvent of tetrahydrofuran and triethylborane hexane solution,acetonitrile, 1,4-dioxane, tetrahydrofuran (THF) and the like. Inparticular, a mixed solvent of tetrahydrofuran and triethylborane hexanesolution is preferable. The amount of solvent is preferably in the rangeof 0.5 to 5 L, more preferably 1 to 2 L, with respect to 1 mol of thecompound of general formula (6).

The reaction temperature for this step, which varies depending upon thekind of solvent, is preferably in the range of 0 to 120° C., morepreferably, room temperature. It is preferable to carry out the reactionwithin the above-mentioned temperature range from the viewpoint ofyield. In this step, the reaction time is typically in the range of 0.1to 10 hours, preferably 1 to 50 hours. To cause the reaction within theabove-mentioned time range produces good results in terms of yield. Thisstep can preferably give the D4I in high yields.

After the completion of the reaction in this step, the obtained productmay be further purified by chromatography or the like.

(viii) In the present invention, DDI (7) can also be obtained bysubjecting the D41 (4) prepared through the step (vii) to hydrogenation,using the technique known in the art (refer to, for example, Chu, C. K.et al. J. Org. Chem. 1989, 54, 2217-2225).

The catalyst that can be used in this step and the amount thereof, thesolvent that can be used in this step and the amount thereof, thereaction temperature, and the reaction time are the same as thosedescribed in the conditions of the step (iii), and the preferableconditions and the reasons therefor described in the step (iii) are alsoapplied to this case.

The D4I (4) or the inosine derivative represented by general formula (2)can be produced by following the sequence of the steps combined as shownbelow: (i)-(ii)-(iii), (i)-(ii)-(v), or (i)-(vi)-(vii). In particular,the D4I can preferably be obtained in remarkably high yields byfollowing the steps of (i), (vi) and (vii) in this order, using as theraw material an inosine derivative of general formula (3) where R1 isp-methoxybenzyl group.

After the D4I or the inosine derivative represented by general formula(2) is obtained by any of the aforementioned combinations of the steps,the additional step (iv) or (viii) can provide the DDI (7). Namely, theDDI can be produced by following the sequence of the steps combined asshown below: (i)-(ii)-(iii)-(iv), (i)-(ii)-(v)-(viii), or(i)-(vi)-(vii)-(viii). In particular, the DDI can preferably be obtainedin remarkably high yields by following the steps of (i), (vi), (vii) and(viii) in this order, using as the raw material an inosine derivative ofgeneral formula (3) where R1 is p-methoxybenzyl group.

After the completion of the reactions in the present invention, theobtained product may further be purified by conventional processes, suchas chromatography, crystallization and the like to obtain a targetedDDI.

The present invention will now be explained in detail with reference tothe following Examples.

EXAMPLES Example 1 Synthesis of N¹,5′-O-dibenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine

To a dimethyl sulfoxide solution (1 mL) of N¹,5′-O-dibenzyl inosine (224mg, 0.5 mmol) synthesized in accordance with a method described inLuzzio, F. A. et al. J. Org. Chem., 1994, 59, 7267-7272, an aqueoussolution of sodium hydroxide (0.28 mL, 1.1 mmol) at a concentration of4.0 mol/L and carbon disulfide (0.09 mL, 1.5 mmol) were added, and theobtained mixture was stirred at room temperature for 2 hours. To theobtained solution, methyl iodide (0.07 mL, 1.1 mmol) was added dropwise,the mixture was then stirred at room temperature for one hour. Then,with the addition of ethyl acetate (10 mL) and water (2 mL), thereaction was terminated. After the layers were separated, the resultantwater layer was again extracted by the addition of ethyl acetate (10mL). The two organic layers thus obtained were combined and dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. After purification by chromatography (using 15 g of silica geland a mixed solvent of hexane and ethyl acetate (1:2) as an elutingsolution), 276 mg of the intended product was obtained in a yield of 88%as a colorless oily material.

¹H-NMR (CDCl₃): δ 2.53 (s, 3H), δ 2.60 (s, 3H), δ 3.75-3.90 (m, 2H), δ4.58 (m, 1H), δ 4.63 (s, 2H), δ 5.25 (s, 1H), δ 6.44 (m, 2H), δ 6.62 (m,1H), δ 7.25-7.39 (m, 10H), δ 7.96 (s, 1H), δ 8.01 (s, 1H). ¹³C—NMR(CDCl₃): δ 19.79, 19.88, 49.58, 69.68, 74.30, 79.55, 80.87, 83.56,85.60, 125.11, 128.05, 128.35, 128.55, 128.71, 129.03, 129.41, 136.35,137.40, 138.76, 147.81, 148.02, 156.84, 214.71, 215.05. ESIMS m/z: 629(M+H).

Example 2 Synthesis ofN¹,5′-O-dibenzyl-2′,3′-didehydro-2′,3′-dideoxyinosine

An acetonitrile solution (1 mL) ofN¹,5′-O-dibenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine (314 mg,0.5 mmol) was heated to 80° C. To this solution, an acetonitrilesolution (1 mL) of N-ethylpiperidine hypophosphite (358 mg, 2 mmol) and2,2′-azobisisobutyronitrile (16.4 mg, 0.1 mmol) were added, and themixture was then stirred at 90° C. for one hour. After the reactionmixture was cooled, the reaction was terminated with the addition ofwater (3 mL). The reaction mixture was extracted by the addition ofethyl acetate (15 mL), and the resultant organic layer was dried overanhydrous magnesium sulfate and concentrated under reduced pressure.After purification by chromatography (using 12 g of silica gel and amixed solvent of hexane and ethyl acetate (1:2) as an eluting solution),150 mg of the intended product was obtained in a yield of 71% as acolorless oily material.

¹H-NMR (CDCl₃): δ 3.61 (d, 2H, J=3.8 Hz), δ 4.45 (d, 1H, J=12.2 Hz), δ4.54 (d, 1H, J=12.2 Hz), δ 5.06 (m, 1H), δ 5.25 (d, 1H, J=14.7 Hz), δ5.31 (d, 1H, J=14.7 Hz), δ 6.01 (d, 1H, J=6.0 Hz), δ 6.40 (d, 1H, J=6.0Hz), δ 6.98 (s, 1H), δ 7.21-7.37 (m, 10H), δ 8.00 (s, 1H), δ 8.03 (s,1H). ¹³C-NMR (CDCl₃): δ 49.47, 71.13, 73.82, 86.89, 88.54, 124.80,125.38, 128.27, 128.48, 128.62, 128.71, 128.87, 129.36, 135.02, 136.56,137.82, 139.24, 147.65, 147.69, 157.04. ESIMS m/z: 417 (M+H).

Example 3 Synthesis of N¹,5′-O-dibenzyl-2′,3′-dideoxyinosine

To a methanol solution (1 mL) ofN¹,5′-O-dibenzyl-2′,3′-didehydro-2′,3′-dideoxyinosine (207 mg, 0.5mmol), 5% palladium-carbon (20 mg) was added, and the mixture wasstirred at room temperature for 2 hours in an atmosphere of hydrogen (1atm). The palladium catalyst was removed from the obtained reactionmixture by filtration, and the resultant filtrate was concentrated underreduced pressure. After purification by chromatography (using 15 g ofsilica gel and ethyl acetate as an eluting solution), 187 mg of theintended product was obtained in a yield of 90% as a white solid.

¹H-NMR (CDCl₃): δ 2.08-2.17 (m, 2H), δ 2.40-2.49 (m, 2H), δ 3.59 (d-d,1H, J=10.5, 4.4 Hz), δ 3.73 (d-d, 1H, J=10.5, 3.3 Hz), δ 4.30-4.40 (m,1H), δ 4.55 (d, 1H, J=12.2 Hz), δ 4.60 (d, 1H, J=12.2 Hz), δ 5.24 (d,1H, J=14.7 Hz), δ 5.28 (d, 1H, J=14.7 Hz), δ 6.24 (d-d, 1H, J=6.5, 3.3Hz), δ 7.27-7.37 (m, 10H), δ 7.97 (s, 1H), δ 8.14 (s, 1H). ¹³C-NMR(CDCl₃): δ 26.43, 33.58, 49.43, 71.48, 73.90, 81.20, 85.78, 125.29,128.20, 128.26, 128.41, 128.52, 128.91, 129.38, 136.55, 138.05, 138.83,147.08, 147.16, 157.04. ESIMS m/z: 415 (M+H).

Example 4 Synthesis of 2′,3′-dideoxyinosine (DDI)

To a N,N-dimethylformamide solution (1 mL) ofN¹,5′-O-dibenzyl-2′,3′-dideoxyinosine (52 mg, 0.125 mmol), an aqueoussolution of sodium hydroxide (0.3 mL) at a concentration of 1 mol/L wasadded, and the mixture was stirred at room temperature for 2 hours. Tothe obtained solution, 20% palladium hydroxide-carbon (10 mg) was added,and the mixture was stirred at room temperature for 2 hours in anatmosphere of hydrogen (1 atm) and thereafter stirred at 80° C. for 16hours and at 100° C. for 6 hours. The palladium catalyst was removedfrom the obtained reaction mixture by filtration, and the resultantfiltrate was concentrated under reduced pressure. After purification bychromatography (using 10 g of silica gel and a mixed solvent ofdichloromethane and methanol (4:1) as an eluting solution), 21 mg of theintended product was obtained in a yield of 70% as a white solid.

¹H-NMR (DMSO-d₆): δ 2.00-2.07 (m, 2H), δ 2.31-2.53 (m, 2H), δ 3.52 (m,1H), δ 3.62 (m, 1H), δ 4.11 (m, 1H), δ 4.96 (m, 1H), δ 6.21 (d-d, 1H,J=6.8, 3.3 Hz), δ 8.05 (s, 1H), δ 8.33 (s, 1H). ¹³C-NMR (DMSO-d₆): δ25.77, 32.49, 62.96, 82.40, 84.80, 124.64, 138.54, 145.97, 147.94,156.98. ESIMS m/z: 237 (M+H).

Example 5 Synthesis ofN¹,5′-O-di-p-methoxybenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine

To a N,N-dimethylformamide solution (5 mL) of N¹,5′-O-di-p-methoxybenzylinosine (400 mg, 0.78 mmol) synthesized in accordance with a methoddescribed in Luzzio, F. A. et al. J. Org. Chem., 1994, 59, 7267-7272, a60% mineral oil dispersion of sodium hydride (94 mg, 2.34 mmol) wasadded and the obtained mixture was stirred at room temperature for 2hours, and thereafter carbon disulfide (0.48 mL, 7.88 mmol) was addedthereto and the obtained mixture was stirred at room temperature for 12hours. With the addition of methyl iodide (0.5 mL, 7.88 mmol), theobtained solution was stirred at room temperature for 3 hours. Then, thereaction mixture was concentrated under reduced pressure and dilutedwith ethyl acetate. The resultant organic layer was washed with water,and thereafter dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. After purification by chromatography (using aseluting solutions a mixed solvent of hexane and ethyl acetate (1:1), amixed solvent of hexane and ethyl acetate (3:7), and ethyl acetatesuccessively in this order), 484 mg of the intended product was obtainedin a yield of 82%. ¹H NMR (CDCl₃): δ 2.50 (s, 6H), δ 2.89 (s, 2H), δ2.96 (s, 2H), δ 3.80 (s, 6H), δ 4.69-4.87 (m, 3H), δ 5.71-5.81 (m, 1H),δ 6.13 (m, 1H), δ 6.29 (m, 1H), δ 6.84-6.92 (m, 4H), δ 7.15-7.36 (m,4H), δ 7.88 (s, 1H), δ 8.04 (s, 1H).

Example 6 Synthesis ofN¹,5′-O-di-p-methoxybenzyl-2′,3′-didehydro-2′,3′-dideoxyinosine

To a 1,4-dioxane solution of N-ethylpiperidine hypophosphite (2.04 mL,3.6 mmol) at a concentration of 1.764 mol/L, a mixed solution of atetrahydrofuran solution (3 mL) containingN¹,5′-O-di-p-methoxybenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine(250 mg, 0.36 mmol) and a triethylborane hexane solution (0.36 mL, 0.36mmol) at a concentration of 1.0 mol/L was added, and the obtainedmixture was stirred at room temperature for one hour. The obtainedreaction mixture was diluted with ethyl acetate. The resultant organiclayer was washed with brine solution, and thereafter dried overanhydrous magnesium sulfate and concentrated under reduced pressure.After purification by chromatography (using as eluting solutions a mixedsolvent of hexane and ethyl acetate (3:7), ethyl acetate, and a mixedsolvent of dichloromethane and methanol (10:1) successively in thisorder), 169 mg of the intended product was obtained in a yield of 98%.¹H NMR (CDCl₃): δ 2.89 (s, 2H), δ 2.97 (s, 2H), δ 3.79 (s, 6H), δ 3.9(m, 2H), δ 4.51 (m, 1H), δ 4.87 (m, 1H), δ 5.95 (m, 1H), δ 6.81 (m, 1H)δ 6.78-6.90 (m, 4H), δ 7.10-7.39 (m, 4H), δ 7.99 (s, 1H), δ 8.01(s, 1H).

Example 7 Synthesis of 2′,3′-didehydro-2′,3′-dideoxyinosine (D4I)

To an acetonitrile-water mixed (3:1) solution (5 mL) containingN¹,5′-O-di-p-methoxybenzyl-2′,3′-didehydro-2′,3′-dideoxyinosine (150 mg,0.32 mmol), diammonium cerium (IV) nitrate (526 mg, 0.96 mmol) wasadded, and the obtained mixture was stirred at room temperature for 3hours. The obtained reaction mixture was diluted with ethyl acetate. Theresultant organic layer was washed with brine solution, and thereafterdried over anhydrous magnesium sulfate and concentrated under reducedpressure, whereby 75 mg of the intended product was obtained in a yieldof 99%. ¹H NMR (DMSO-d₆): δ 3.57 (m, 2H), δ 4.89 (m, 1H), δ 6.14 (m,1H), δ 6.48 (m, 1H), δ 6.91 (m, 1H), δ 8.08 (s, 1H), δ 8.11 (s, 1H).

Example 8 Synthesis of 2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine

To an acetonitrile-water mixed (3:1) solution (4 mL) containingN¹,5′-O-di-p-methoxybenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine(151 mg, 0.22 mmol), diammonium cerium (IV) nitrate (362 mg, 0.66 mmol)was added, and the obtained mixture was stirred at room temperature for3 hours. The obtained reaction mixture was diluted with ethyl acetate.The resultant organic layer was washed with brine solution, andthereafter dried over anhydrous magnesium sulfate and concentrated underreduced pressure, whereby 99 mg of the intended product was obtained ina yield of 99%. ¹H NMR (DMSO-d₆): δ 2.50 (s, 6H), δ 3.59 (m, 2H), δ 4.95(m, 1H), δ 5.18 (m, 1H) δ 6.11 (m, 1H), δ 6.25 (m, 1H), δ 7.89 (s, 1H),δ 8.04 (s, 1H).

Example 9 Synthesis of 2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine

To a dichloromethane-water mixed (18:1) solution (7.2 mL) containingN¹,5′-O-di-p-methoxybenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine(151 mg, 0.22 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (150 mg,0.66 mmol) was added, and the obtained mixture was stirred at roomtemperature for 3 hours. The obtained reaction mixture was diluted withethyl acetate. The resultant organic layer was washed with brinesolution, and thereafter dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. After purification bychromatography (using as eluting solutions mixed solvents of hexane andethyl acetate at concentrations of 1:1, 3:7, and 2:8 successively inthis order), 87 mg of the intended product was obtained in a yield of88%.

Example 10 Synthesis of 2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine

To a tetrahydrofuran solution (10 mL) containingN¹,5′-O-di-p-methoxybenzyl-2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine(151 mg, 0.22 mmol), 10% palladium-carbon (23 mg) was added, and theobtained mixture was stirred at room temperature for 2 days in anatmosphere of hydrogen (1 atm). The palladium catalyst was removed fromthe obtained reaction mixture by filtration, and the resultant filtratewas concentrated under reduced pressure. After purification bychromatography (using as eluting solutions mixed solvents of hexane andethyl acetate at concentrations of 1:1, 3:7, and 2:8 successively inthis order), 42 mg of the intended product was obtained in a yield of43%.

Example 11 Synthesis of 2′,3′-didehydro-2′,3′-dideoxyinosine (D4I)

To a 1,4-dioxane solution containing N-ethylpiperidine hypophosphite(1.25 mL, 2.2 mmol) at a concentration of 1.764 mol/L, a mixed solutionof a tetrahydrofuran solution (2 mL) of2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine (99 mg, 0.22 mmol) and atriethylborane hexane solution (0.22 mL, 0.22 mmol) at a concentrationof 1.0 mol/L was added, and the obtained mixture was stirred at roomtemperature for one hour. The obtained reaction mixture was diluted withethyl acetate. The resultant organic layer was washed with brinesolution, and thereafter dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. After purification bychromatography (using as eluting solutions a mixed solvent of hexane andethyl acetate (3:7), ethyl acetate, and a mixed solvent ofdichloromethane and methanol (10:1) successively in this order), 47 mgof the intended product was obtained in a yield of 92%.

According to the production methods of the present invention, DDI caninexpensively be synthesized in satisfactory yields through thecurtailed steps. As a result, the value of the present invention can beenhanced because the production of compounds useful as the anti-AIDSdrugs can be achieved on industrial scale.

1. A method for producing 2′,3′-dideoxyinosine, comprising:hydrogenating an inosine compound represented by formula (1) or aninosine compound represented by formula (2):

wherein each R1 in formulae (1) and (2) may be the same or different andis a benzyl group, a benzhydryl group, or a trityl group, each of whichmay have a substituent.
 2. A method for producing2′,3′-didehydro-2′,3′-dideoxyinosine represented by formula (4):

comprising: eliminating both substituents R1 from an inosine compoundrepresented by formula (1):

wherein each R1 may be the same or different and is a benzyl group, abenzhydryl group, or a trityl group, each of which may have asubstituent.
 3. A method for producing 2′,3′-dideoxyinosine, comprising:(a) subjecting an inosine compound represented by formula (3):

to dithiocarbonylation to obtain a compound represented by formula (5):

(b) radically reducing said compound represented by formula (5) toobtain an inosine compound represented by formula (1):

(c) hydrogenating the said inosine compound represented by formula (1)to obtain a compound represented by formula (2):

wherein each R1 in formulae (1), (2), (3), and (5) may be the same ordifferent and is a benzyl group, a benzhydryl group, or a trityl group,each of which may have a substituent; and each R2 in formula (5) isindependently an alkylthio group having 1 to 12 carbon atoms, an alkoxylgroup having 1 to 12 carbon atoms or an alkylamino group having 1 to 12carbon atoms; and (d) eliminating substituents R1 from compoundrepresented by formula (2).
 4. A production method according to claim 3,wherein each R1 in formulae (1), (2), (3), and (5) is independently abenzyl group having as a substituent an alkoxyl group with 1 to 12carbon atoms or unsubstituted benzyl group, and each R2 in formula (5)is independently an alkylthio group having 1 to 12 carbon atoms.
 5. Amethod for producing 2′,3′-didehydro-2′,3′-dideoxyinosine represented byformula (4):

comprising: (a) subjecting an inosine compound represented by formula(3):

to dithiocarbonylation to obtain a compound represented by formula (5):

(b) eliminating substituents R1 from said compound represented byformula (5) to obtain a compound represented by formula (6):

wherein each R1 in formulae (3) and (5) may be the same or different andis a benzyl group, a benzhydryl group or a trityl group, each of whichmay have a substituent, and each R2 in formulae (5) and (6) isindependently an alkylthio group having 1 to 12 carbon atoms, an alkoxylgroup having 1 to 12 carbon atoms or an alkylamino group having 1 to 12carbon atoms; and (c) radically reducing the said compound ofrepresented by formula (6).
 6. A method for according to claim 5,wherein each R1 in formulae (3) and (5) is independently a benzyl grouphaving as a substituent an alkoxyl group with 1 to 12 carbon atoms orunsubstituted benzyl group, and each R2 in formulae (5) and (6) isindependently an alkylthio group having 1 to 12 carbon atoms.
 7. Amethod according to claim 5, wherein each R1 in formulae (3) and (5) isindependently a benzyl group having as a substituent an alkoxyl groupwith 1 to 12 carbon atoms.
 8. A method for according to claim 5, whereineach R1 in formulae (3) and (5) is a methoxybenzyl group.
 9. A methodfor according to claim 5, wherein each R1 in formulae (3) and (5) is ap-methoxybenzyl group, and each R2 in formulae (5) and (6) is amethylthio group.
 10. A method for producing 2′,3′-dideoxyinosine,comprising: (a) subjecting an inosine compound represented by formula(3):

to dithiocarbonylation to obtain a compound of represented by formula(5):

(b) eliminating substituents R1 from said compound represented byformula (5) to obtain a compound represented by formula (6):

wherein each R1 in formulae (3) and (5) may be the same or different andis a benzyl group, a benzhydryl group or a trityl group, each of whichmay have a substituent, and each R2 in formulae (5) and (6) isindependently an alkylthio group having 1 to 12 carbon atoms, an alkoxylgroup having 1 to 12 carbon atoms or an alkylamino group having 1 to 12carbon atoms; and (c) radically reducing said compound represented byformula (6) to obtain 2′,3′-didehydro-2′,3′-dideoxyinosine representedby formula (4):

(d) hydrogenating said 2′,3′-didehydro-2′,3′-dideoxyinosine.
 11. Amethod for producing 2′,3′-didehydro-2′,3′-dideoxyinosine represented byformula (4):

comprising: (a) subjecting an inosine compound represented by formula(3):

to dithiocarbonylation to obtain a compound represented by formula (5):

(b) subjecting said compound represented by formula (5) to radicalreduction to obtain an inosine compound represented by formula (1):

wherein each R1 in formulae (1), (3), and (5) may be the same ordifferent and is a benzyl group, a benzhydryl group or a trityl group,each of which may have a substituent, and each R2 in formulae (5) isindependently an alkylthio group having 1 to 12 carbon atoms, an alkoxylgroup having 1 to 12 carbon atoms or an alkylamino group having 1 to 12carbon atoms in the formula (5); and (c) eliminating substituents R1from said inosine compound represented by formula (1).
 12. A method foraccording to claim 11, wherein each R1 in formulae (1), (2), and (5) isindependently a benzyl group having as a substituent an alkoxyl groupwith 1 to 12 carbon atoms or unsubstituted benzyl group, and each R2 informula (5) is independently an alkylthio group having 1 to 12 carbonatoms in the formula (5).
 13. A method for according to claim 11,wherein each R1 in formulae (1), (3), and (5) is independently a benzylgroup having as a substituent an alkoxyl group with 1 to 12 carbonatoms.
 14. A method for according to claim 11, wherein each R1 informulae (1), (3), and (5) is a methoxybenzyl group.
 15. A method foraccording to claim 11, wherein each R1 in formulae (1), (3), and (5) isa p-methoxybenzyl group, and each R2 in formula (5) is a methylthiogroup.
 16. A method for producing 2′,3′-dideoxyinosine, comprising: (a)subjecting an inosine compound represented by formula (3):

to dithiocarbonylation to obtain a compound represented by formula (5):

(b) subjecting said compound represented by formula (5) to radicalreduction to obtain an inosine compound represented by formula (1):

wherein each R1 in formulae (1), (3), and (5) may be the same ordifferent and is a benzyl group, a benzhydryl group or a trityl group,each of which may have a substituent, and each R2 in formula (5) isindependently an alkylthio group having 1 to 12 carbon atoms, an alkoxylgroup having 1 to 12 carbon atoms or an alkylamino group having 1 to 12carbon atoms; (c) eliminating substituents R1 from said inosine compoundrepresented by formula (1) to obtain2′,3′-didehydro-2′,3′-dideoxyinosine represented by formula (4)

(d) hydrogenating said 2′,3′-didehydro-2′,3′-dideoxyinosine.
 17. Aninosine compound represented by formula (6):

wherein each R2 is independently an alkylthio group having 1 to 12carbon atoms, an alkoxyl group having 1 to 12 carbon atoms or analkylamino group having 1 to 12 carbon atoms.
 18. An inosine compoundaccording to claim 17, wherein each R2 is independently an alkylthiogroup having 1 to 12 carbon atoms.